Zoledronate rescues immunosuppressed monocytes in sepsis patients

Abstract

Summary Severe sepsis is often accompanied by a transient immune paralysis, which is associated with enhanced susceptibility to secondary infections and poor clinical outcomes. The functional impairment of antigen‐presenting cells is considered to be a major hallmark of this septic immunosuppression, with reduced HLA‐DR expression on circulating monocytes serving as predictor of mortality. Unconventional lymphocytes like γδ T‐cells have the potential to restore immune defects in a variety of pathologies including cancer, but their use to rescue sepsis‐induced immunosuppression has not been investigated. Our own previous work showed that Vγ9/Vδ2+ γδ T‐cells are potent activators of monocytes from healthy volunteers in vitro, and in individuals with osteoporosis after first‐time administration of the anti‐bone resorption drug zoledronate in vivo. We show here that zoledronate readily induces upregulation of HLA‐DR, CD40 and CD64 on monocytes from both healthy controls and sepsis patients, which could be abrogated by neutralising the pro‐inflammatory cytokines interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α in the cultures. In healthy controls, the upregulation of HLA‐DR on monocytes was proportional to the baseline percentage of Vγ9/Vδ2 T‐cells in the peripheral blood mononuclear cell population. Of note, a proportion of sepsis patients studied here did not show a demonstrable response to zoledronate, predominantly patients with microbiologically confirmed bloodstream infections, compared with sepsis patients with more localised infections marked by negative blood cultures. Taken together, our results suggest that zoledronate can, at least in some individuals, rescue immunosuppressed monocytes during acute sepsis and thus may help improve clinical outcomes during severe infection.

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

“…Sepsis is a systemic inflammatory response syndrome caused by infection and is one of the leading causes of death worldwide (1)(2)(3). It is a complex disease characterized by severe systemic inflammation and multiple organ dysfunction (e.g., blood vessels, lungs, liver, kidneys, heart, and brain) due to the host's unregulated response to infection (4,5). Multidrug-resistant bacteria, drug side effects and adverse events make the treatment of sepsis considerably complex (2,(6)(7)(8)(9).…”

Immune Dysfunction is Associated with Readmission in Survivors of Sepsis Following Infected Pancreatic Necrosis

“… 12 , 28 , 29 Furthermore, the reduction of mHLA-DR was demonstrated to be an independent risk factor of nosocomial infection and mortality. 30 In previous studies conducted in AP patients, a reduced proportion of mHLA-DR in the early stage was associated with increased disease severity, development of secondary infection, or decreased survival, raising an association between immunosuppression and poor in-hospital prognosis. 3–9 Early in 2004, Mentula et al 4 have studied 74 patients with acute pancreatitis (AP) admitted within 72 h after symptom onset and found that a reduced proportion of mHLA-DR was associated with secondary infection of pancreatic necrosis.…”

Conventional and unconventional T cell responses contribute to the prediction of clinical outcome and causative bacterial pathogen in sepsis patients

“…A total of 77 patients were enrolled between 2018 and 2021 who were over 18 years old with a diagnosis of sepsis according to the Third International Consensus Definitions for Sepsis and Septic Shock (‘Sepsis-3’) [45]. They were cared for in the intensive care unit at the University Hospital of Wales in Cardiff, and were recruited within 36 hours of the presumed onset of infective illness when they already had or would require arterial cannulation as part of standard treatment [46]. Patients were excluded if they were pregnant or breastfeeding, or were females of childbearing age in whom a pregnancy test had not been performed; had severe immune deficiency ( e.g.…”